1. Technical Field
The present invention is related to a pharmaceutical composition and a method for treating pathological changes induced by high doses of retinoids. More particularly, the present invention is related to the use of rescuing agents for ameliorating retinoid induced pathogenesis, the rescuing agents being a group of substances which prevent formation of fatty liver.
2. Prior Art
Retinoids are lipophilic compounds possessing chemical and biological similarities to vitamin A. Retinoids mainly affect epithelial cells, both in vitro and in vivo and are critical for differentiation and maintenance of all epithelial tissues. Retinoid deficiency causes avitaminosis-A, which can be reversed by low doses of a suitable retinoid. At much higher doses, retinoids are employed for treating dermatological problems ranging from acne to psoriasis to skin cancer (Peck, Drugs 24: 341-351, 1982). In addition, retinoids have potential use in prevention of chemical carcinogenesis (Sporn, et al., Federation Proceedings 35: 1332-1338, 1976; Bolag, Cancer Chemother. Pharmacol. 3, 207-215, 1979) and in treatment of rheumatoid arthritis (Brinkerhoff, et al., Science 221, 756-758, 1983). However, at the therapeutic doses required for treating dermatological and other problems or ailments, retinoids evoke distinct pathological changes.
The pathological changes or the toxic symptoms of retinoids induced in humans are similar to those in experimental animals. Thus, in man, the symptoms of retinoid toxicity include weight loss, dry and chapping skin, dryness of the oral mucosa, facial dermatitis, conjunctivitis, and hair loss (Peck, supra). In mice high doses of retinoids were seen to cause loss of weight, skin scaling, loss of hair, and bone fracture (Bolag, Europ. J. Cancer 10: 731-737, 1974). These reports clearly demonstrate the symptomalogical similarities of retinoid pathogenesis in humans and mice.
It has been reported that although various retinoids may differ in relative bioeffectiveness, their toxic symptoms are quite similar. For example, a natural compound, 13-trans retinoic acid, and its synthetic aromatic analog, etretinate, differ in the dose required to induce pathological changes, but do not differ in the pathological changes induced (Bolag, supra). It has been suggested that the similarity of toxic effects may be based at least in part on metabolic interconversion of these compounds (McCormick, et al., Biochemistry 22: 3933-3940, 1983).
It has also been reported that different modes of application of retinoids also result in analogous toxic symptoms (Bolag and Peck, supra). Hence, it is not possible to avoid the systemic pathological effects of retinoids by changing the mode of application, e.g. by topical application rather than oral administration.
To enable better therapeutic usage of retinoids various chemically modified compounds of this class have been prepared and evaluated (Pawson, et al., J. Med. Chem. 25: 1269-1277, 1982). Currently three of these retinoids are known to be used in humans: tretinoin (13-trans-retinoic acid); isotretinoin (13-cis-retinoic acid) and etretinate (all-trans-9-(4-methoxy-2,3,3-trimethylphenyl)-3,7-dimethyl-2,4,6,8-nonate traemoate). It has been reported that the toxic effects of 13-cis-retinoic acid can be lowered by adjusting specific dosage regimens (Peck, U.S. Pat. No. 4,322,438).
In another approach to the problem, the toxicity of several retinoids was decreased by increasing their water solubility through formation of complexes (Pitha, U.S. Pat. No. 4,371,673, Pitha, et al., Life Sciences 32: 719-723, 1983).
The Applicant has now discovered that the pathological or toxic effects of retinoids can be substantially reduced by administering a compound selected from the group consisting of agents which prevent formation of fatty liver.